Zanamivir is an orally inhaled powder currently approved
in 19 countries for the treatment of, and in two for the prophylaxis of influenza A and B. Zanamivir
is a competitive inhibitor of the neuraminidase glycoprotein, which is essential in the infective
cycle of influenza viruses. It closely mimics sialic acid, the natural substrate of the
neuraminidase (

Over the last few years, a number of events have resulted in changes to the
zanamivir prescribing information which now contains warnings of bronchospasm, dyspnoea, rash,
urticaria and allergic type reactions, including facial and oropharyngeal oedema. However, apart
from these rare episodes, the drug has a good safety profile if begun early (

The chemical name of zanamivir is
5-(acetylamino)-4-[(aminoiminomethyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-en
onic acid. It has the following structural formula:

Pharmacokinetics

Data on orally inhaled zanamivir indicate that
10-20 % of the active compound reaches the lungs. The rest is deposited in the oropharynx and
approximately 4 % to 17 % of the inhaled dose is systemically absorbed. The peak serum
concentrations are reached within 1 to 2 hours following a 10 mg dose. Plasma protein
binding is limited (< 10 %). Zanamivir is excreted unchanged in the urine with the
excretion of a single dose completed within 24 hours (

Cass 1999b). The serum half-life of
zanamivir after administration by oral inhalation ranges from 2.5 to 5.1 hours.

Studies have demonstrated that intravenously administered zanamivir is
distributed to the respiratory mucosa and is protective against infection and illness following
experimental human influenza A virus inoculation (

Zanamivir has a good safety profile and the overall risk
of occurrence of any respiratory event is low (

Loughlin 2002). Results from in vitro
and in vivo animal studies suggest that zanamivir has low acute toxicity and no significant systemic
toxicity or respiratory tract irritancy at plasma exposures more than 100-fold higher than those
anticipated following clinical use (Freund
1999).

Recommended dosages of zanamivir usually do not adversely affect pulmonary
function in patients with respiratory disorders. However, in some patients, bronchospasm and a
decline in lung function (FEV

1 or peak expiratory flow) have
been reported after usage of zanamivir. In most cases, these patients had underlying pulmonary
conditions such as asthma or chronic obstructive pulmonary disease. Because of the risk of serious
adverse events, zanamivir is not generally recommended for the treatment of patients with underlying
airways disease. Zanamivir should also be discontinued in patients who develop bronchospasm or who
have a decline in respiratory function. If symptoms are severe, immediate treatment and
hospitalisation may be required.

Allergic reactions, including oropharyngeal oedema and serious skin rashes may
rarely occur during treatment with zanamivir. In these cases, the drug should be stopped and
appropriate treatment instituted.

The frequency of other side effects has been reported to be roughly identical in
both treatment and placebo groups: diarrhoea, nausea, dizziness, headaches, less frequently malaise,
abdominal pain, and urticaria occurred at similar frequencies and could be related to lactose
vehicle inhalation. The most frequent laboratory abnormalities in Phase 3 treatment studies included
elevations of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar
proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness
(

However, in children aged 5 to 12 years, nasal signs and symptoms (zanamivir
20 %, placebo 9 %), cough (zanamivir 16 %, placebo 8 %), and throat/tonsil
discomfort and pain (zanamivir 11 %, placebo 6 %) were reported more frequently with
zanamivir than placebo. In a subset with chronic respiratory disease, lower respiratory adverse
events (described as asthma, cough, or viral respiratory infections which could include
influenza-like symptoms) were reported in 7 out of 7 zanamivir recipients and 5 out of 12 placebo
recipients

.

The following adverse reactions have been identified
during post-marketing use of zanamivir, but it is not possible to reliably estimate their frequency
or establish a cause relationship to zanamivir exposure (

Zanamivir has not been studied in pregnant women. In animal studies, zanamivir
has not been shown to cause birth defects or other problems.

In rats, zanamivir is excreted in milk, but zanamivir has not been studied in
nursing mothers and there is no information as to the possible excretion of zanamivir in human
milk.

Efficacy

Inhaled zanamivir reduces the median time to alleviation
of major influenza symptoms by up to 2.5 days if taken within 48 h of symptom onset. These
benefits appear to be particularly marked in severely ill patients and in individuals
≥ 50 years of age, who have underlying illnesses, or who are considered high risk.
Patients with a lower temperature or less severe symptoms appear to derive less benefit from
treatment with zanamivir.

When used for prophylaxis, zanamivir significantly reduces the number of families
with new cases of influenza compared with placebo, and prevented new cases of influenza in long-term
care facilities.

Treatment

The first clinical experience with zanamivir included
patients from separate randomised, double-blind studies in 38 centres in North America and 32
centres in Europe in 1994-1995. These studies demonstrated approximately a one-day reduction in the
time to alleviation of symptoms in treated patients (4 vs. 5 days) (

Hayden
1997). An even larger treatment benefit (3 days) was seen in patients
who had severe symptoms at entry (Monto
1999). A 3 day treatment benefit was also observed in patients aged
> 50 years, compared with 1 day in patients aged < 50 years. In
"high-risk" patients there was a treatment benefit of 2.5 days (Monto
1999). In addition, zanamivir has been shown to be effective in patients at
risk of developing influenza-related complications such as age ≥ 65 years and the
presence of underlying chronic disease including asthma, chronic obstructive pulmonary disease,
cardiovascular disease, diabetes mellitus, and immunocompromise (Lalezari
2001).

Influenza infections may lead to respiratory tract complications that result in
antibiotic treatment. A meta-analysis of 7 clinical trials reported that 17 % of placebo
recipients developed a respiratory event leading to antibiotic use, mainly for acute bronchitis or
acute sinusitis, whereas among zanamivir-treated patients the incidence of respiratory events
leading to the use of antimicrobials was 11 % (

Kaiser
2000b). However, these finding have not remained unquestioned. In the
setting of a large managed care plan (> 2,300 patients treated), the patterns of influenza
complications were found to be similar in zanamivir-treated and untreated patients (Cole 2002).

Prophylaxis

A series of randomised trials have proven the efficacy of
zanamivir in the prevention of influenza. In a study involving healthy adults, 10 mg once a day
or placebo was administered by oral inhalation at the start of the influenza outbreak. Prophylaxis
continued for a 4-week period. Zanamivir was 67 % efficacious in preventing clinical influenza
(6 % [34/554] clinical influenza in the placebo group vs. 2 % [11/553] in the zanamivir
group) and 84 % efficacious in preventing illnesses with fever (

Another clinical trial enrolled families with two to five members and at least
one child who was five years of age or older. As soon as an influenza-like illness developed in one
family member, the family received either zanamivir (10 mg zanamivir inhaled once daily for
10 days) or placebo. In the zanamivir families, 4 % of families had at least one new
influenza case, compared with 19 % in the placebo families. The median duration of symptoms was
2.5 days shorter in the zanamivir group than in the placebo group (5.0 vs. 7.5 days)
(

Hayden
2000). A similar risk reduction was shown in a study where zanamivir was
administered after close contact with an index case of influenza-like illness (Kaiser 2000).

In a study of inhaled zanamivir for the prevention of influenza in families,
4 % of zanamivir versus 19 % of placebo households had at least 1 contact who developed
symptomatic, laboratory-confirmed influenza (81 % protective efficacy). The protective efficacy
was similarly high for individuals (82 %) and against both influenza types A and B (78 %
and 85 %, respectively, for households) (

In a trial on children aged five to twelve years,
zanamivir reduced the median time to symptom alleviation by 1.25 days compared with placebo.
Zanamivir-treated patients returned to normal activities significantly faster and took significantly
fewer relief medications than placebo-treated patients (

Zanamivir is therefore safe in children - if they can take it. Children,
especially those under 8 years old, are usually unable to use the delivery system for inhaled
zanamivir appropriately (not producing measurable inspiratory flow through the diskhaler or
producing peak inspiratory flow rates below the 60 l/min considered optimal for the device). As
a lack of measurable flow rate is related to inadequate or frankly undetectable serum
concentrations, prescribers should carefully evaluate the ability of young children to use the
delivery system when considering prescription of zanamivir. When zanamivir is prescribed for
children, it should be used only under adult supervision and with attention to proper use of the
delivery system (

Special settings in which zanamivir has been used include
acute lymphoblastic leukemia (

Maeda
2002) and allogeneic stem cell transplantation (Johny 2002). The second report found
no toxicity attributable to zanamivir and rapid resolution of influenza symptoms. There was no
mortality due to influenza in these patients.

Avian Influenza Strains

In a study performed on mice in 2000, zanamivir was shown
to be efficacious in treating avian influenza viruses H9N2, H6N1, and H5N1 transmissible to mammals
(

Development of resistance is rare. To date, no virus
resistant to zanamivir has been isolated from immunocompetent individuals after treatment. In
addition, all zanamivir-resistant strains selected in vitro to date have diminished viability. Known
resistance mutations are both influenza virus subtype and drug specific (

There is evidence for different patterns of susceptibility and cross-resistance
between neuraminidase inhibitors (

Mishin
2005, Yen 2005), but no studies have so far evaluated the risk of emergence of cross-resistance in clinical
practice.

Drug Interactions

Zanamivir is administered via inhalation and the low
level of absorption of the drug results in low serum concentrations and modest systemic exposure to
zanamivir after inhalation. Zanamivir is not metabolised, and the potential for clinically relevant
drug-drug interactions is low (

Cass
1999b). Zanamivir is not a substrate nor does it affect cytochrome P450 (CYP)
isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes (Relenza
2003). There is no theoretical basis for
expecting metabolic interactions between zanamivir and other co-administered compounds (Daniel 1999).

Recommendations for Use

Zanamivir is indicated for the treatment of
uncomplicated acute illness due to influenza A and B viruses in adults and paediatric patients (EU:
12 years or older; US: 7 years and older) who have been symptomatic for no more than
2 days.

Zanamivir is not recommended for the treatment of patients with underlying
airways disease (such as asthma or chronic obstructive pulmonary disease).

Zanamivir (Relenza®) is delivered by inhalation because of its low
oral bioavailability. Each Relenza® Rotadiskcontains 4 double-foil
blisters and each blister contains 5 mg of zanamivir (plus 20 mg of lactose which contains
milk proteins). The contents of each blister are inhaled using a plastic device called a
"Diskhaler". Here, a blister is pierced and zanamivir is dispersed into the air stream
when the patient inhales through the mouthpiece. The amount of drug delivered to the respiratory
tract depends on patient factors such as inspiratory flow.

Patients should be instructed in the use of the delivery system, and instructions
should include a demonstration - which may be difficult in daily medical practice. When prescribed
for children, zanamivir should only be used under adult supervision and instruction.

There has been concern over the ability of elderly people to use the inhaling
device for zanamivir. A study of 73 patients (aged 71 to 99 years) from wards providing
acute elderly care in a large general hospital found that most elderly people could not use the
inhaler device and that zanamivir treatment for elderly people with influenza was unlikely to be
effective (

The recommended dose of zanamivir for the treatment of
influenza in adults and paediatric patients aged 7 years and older is 10 mg bid
(= twice daily 2 consecutive inhalations of one 5-mg blister) for 5 days.

On the first day of treatment, two doses should be taken at least 2 hours
apart. On the following days, doses should be taken about 12 hours apart.

Patients with pulmonary dysfunction should always have a fast-acting
bronchodilator available and discontinue zanamivir if respiratory difficulty develops.

Summary

Trade name:

Relenza®

Drug class: Neuraminidase inhibitor.

Manufacturer: GlaxoSmithKline.

Indications: zanamivir is indicated for the treatment of uncomplicated
acute illness due to influenza A and B viruses in adults and paediatric patients (EU: 12 years
or older; US: 7 years and older) who have been symptomatic for no more than 2 days.

Standard Dosage for Prophylaxis: in most countries, zanamivir has not been
approved for prophylaxis.

Pharmacokinetics: 10 to 20 percent of the active compound reaches the
lungs, the rest is deposited in the oropharynx. 4 % to 17 % of the inhaled dose is
systemically absorbed. Peak serum concentrations are reached within 1 to 2 hours. Limited
plasma protein binding (< 10 %). Excretion of the unchanged drug in the urine. Serum
half-life after administration by oral inhalation is 2.5 to 5.1 hours.

Warning: zanamivir is not recommended for the treatment of patients with
underlying airways disease (such as asthma or chronic obstructive pulmonary disease).

Interactions: no clinically significant pharmacokinetic drug interactions
are predicted based on data from in vitro studies.

Side effects: zanamivir has a good safety profile and the overall risk for
any respiratory event is low.

Patient information: the use of zanamivir for the treatment of influenza
has not been shown to reduce the risk of transmission of influenza to others.

There is a risk of bronchospasm, especially in the setting of underlying airways
disease, and patients should stop zanamivir and contact their physician if they experience increased
respiratory symptoms during treatment such as worsening wheezing, shortness of breath, or other
signs or symptoms of bronchospasm. A patient with asthma or chronic obstructive pulmonary disease
must be made aware of the risks and should have a fast-acting bronchodilator available.

Patients scheduled to take inhaled bronchodilators at the same time as zanamivir
should be advised to use their bronchodilators before taking zanamivir.